The promise of genomic medicine implementation transforming healthcare and improving health will not be realized until discoveries become relevant to and available for use by diverse populations and the clinicians who care for them. Our GeNYC team is prepared to help medical genomics become an innovative, collaborative discipline with inclusiveness, health and health equity at its core. We have decades of experience engaging diverse stakeholders- researchers, patients, clinicians, advocates and entrepreneurs- to conduct chronic disease prevention and control clinical trials in our large health system and network of safety net clinics. In our 16 trials recently mean completed or underway, 80% included primary care or community sites, with a 732 participants/study, 69% were African ancestry (AA) or Latino, 17% refused, and we retained 84%. We chose toharness this expertise to conduct genomic implementation research. At the heart of our team is a Genomics Stakeholder Board. Together, we conducted GUARDD, a multi-site pragmatic clinical trial (PCT) to study effects and challenges of incorporating genetic risk information into primary care. We tested AA adults with hypertension, without diabetes or chronic kidney disease (CKD) for APOL1 high-risk variants nearly exclusive to AAs, that increase kidney failure risk 10-fold. We recruited 2052 AA adults from 15 community and academic primary care practices in NYC, trained lay staff who returned APOL1 results to patients and alerted clinicians of results through clinical decision support in electronic health records (EHRs). Our co-primary outcome, systolic blood pressure (SBP) at 3m (retention rate 93%) reduced by 6mmHg in those told they had high-risk APOL1 genotypes vs. 3mmHg if told they were low-risk (p=0.008). We are now prepared and committed to join IGNITE II and conduct genomic implementation PCTs in diverse settings and populations. We brought a transdisciplinary team together for this purpose, and to study the impact of APO1 risk information on a broader phenotype of AA patients, including those with CKD, who have even higher risk for kidney failure and are often undiagnosed by primary care providers. We aim to: (1) Serve as an enhanced diversity site for IGNITE2, facilitating recruitment and retention of patients into genomic implementation PCTs; and (2) Conduct GUARDD-US, a network-wide PCT expanding GUARDD to AA patients without and with CKD and to other IGNITE sites with different patient and provider populations. We will randomize patients to APOL1 testing vs. waitlist control, and evaluate impact on SBP, renal diagnosis, cost effectiveness and psycho-behavioral outcomes, so results can inform decisions by clinicians, policymakers and payers. If successful, GeNYC may provide a robust framework for future endeavors to implement genomic medicine in diverse clinical practices, validate APOL1 risk-informed management of hypertensive AA patients at high risk of kidney failure, contribute to important efforts to eliminate racial, ethnic and ancestral disparities in health, and show that vulnerable populations can be the first to benefit from genomic discoveries.